Immunological memory is a characteristic feature of the adaptive immune system and is the goal of vaccination against infectious pathogens and cancer. Memory T lymphocytes form the basis of immunological memory through their ability to rapidly eliminate invaders. How memory T lymphocytes develop is not well understood. A major question is how rapidly dividing memory cell precursors escape programmed cell death (PCD) and differentiate into slowly dividing memory cells. We have recently identified Serine protease inhibitor 2A (Spi2A) as a protective factor that when upregulated facilitates the differentiation of memory CDS T Cells by suppressing PCD caused by executioner cathepsin proteases. In the first specific aim we will examine the mechanism of Spi2A upregulation in memory-cell precursors after infection with Lymphocytic choriomeningitis virus (LCMV). We will focus on how the signals transduced through the interleukin-7 receptor (IL-7R) and NF-kappa B transcription factors integrate to control Spi2A express on. In my second specific aim we will generate a conditional mouse model using Cre/LoxP technology in mouse embryonic stem (ES) cells to temporally ablate Spi2A expression. This will allow us to determine the mechanism by which Spi2A suppresses PCD during the development and maintenance of virus spec fie memory CDS T cells. In addition we will examine if Spi2A facilitates the quiescence of memory cells by suppressing cell division. In the third specific aim we will examine the role of Spi2A in the development and maintenance of T helper cell memory cells, which are critical to antibody as well as CDS T cell immunity. The research proposed will lead to improved in vaccination through the induction of potent T cell memory, a goal that up until now has remained elusive for many viruses and cancers.